Laminin-511 and integrin beta-1 in hair follicle development and basal cell carcinoma formation

Here we use a human BCC model system and mouse mutants to re-evaluate the role of laminin-511 in epithelial invagination in the skin. Blocking laminin 511 and 332 in BCCs maintains primary cilia and Shh signalling, but prevents invagination. Similarly, in laminin-511 and dermal beta-1 integrin mutants, dermal papilla development and primary cilia formation are normal. Dermal beta-1 integrin mutants have normal hair follicle development.Our data provides support for a primary role of laminin-511 promoting hair follicle epithelial downgrowth without affecting dermal primary cilia and Shh target gene induction.Hair follicle morphogenesis requires signaling interactions between epithelial cells and adjacent dermal cells that form the specialized mesenchyme called the dermal papilla. During these processes, Sonic hedgehog (Shh) signaling is required in both the epithelial and dermal compartments. Inappropriate epithelial Shh target gene induction is sufficient to cause basal cell carcinoma (BCC), one of the most common tumors in Caucasians, with an incidence of over a million cases per year in the U.S. BCCs also have a striking reliance on adjacent stroma for continued growth and invasion, implying that non-cell autonomous factors influence the extent of Shh target gene induction in tumors [1-3]. Despite extensive study, factors that regulate epithelial-mesenchymal interactions during normal or neoplastic epithelial growth remain poorly understood.The primary cilium is a microtubule-based organelle crucial for the regulation of Shh signalling and growth (for reviews see [4-7]). Receptors positioned within the cilium transduce signals through transcription factors that are activated directly in the cilium or in the cell body. Mutations giving rise to defective primary cilia or improper placement of signaling molecules within the cilium result in a plethora of clinical manifestations [8,9]. In particular, mutations in genes encoding intraflagellar transport proteins impair